Insulin resistance and the metabolic syndrome share risk factors and pathogenetic mechanisms with vascular endothelial dysfunction and atherosclerosis. Sleep disorder breathing (SDB) might be associated with this pathogenetic milieu in complex and intricate ways, both as a consequence (via obesity) and as a cause (via hypoxemia, oxidative stress, and sympathetic overload). The primary objective of this proposal is to study the longitudinal association between SDB and the incidence of the metabolic syndrome and vascular dysfunction in a nested case-cohort sample of participants in the Wisconsin Sleep Cohort (WSC) Study, a community-based sample of middle-age individuals who have undergone repeated full polysomnography studies over the last 15 years, up to four in each participants, four years apart. Additional existing data on these individuals include extensive data on sleep habits, repeat blood pressure measurements (including both sitting and ambulatory blood pressure), anthropometric data, measures of fasting serum glucose, insulin, leptin, ghrelin, inflammatory markers, ApoE-E4, and non-invasive markers of subclinical atherosclerosis (ankle-arm index). A total of 600 participants who have had at least 2 visit in the WSC will be recruited into the study, including a) about 150 cases of incident metabolic syndrome, and b) a random sample of about 450-470 members of the cohort. These participants will undergo non-invasive measures of vascular function in different vascular beds, including: (1) brachial artery reactivity; (2) cerebral artery responsiveness to hypercapnia; and (3) retinal arteriolar/venular ratio. In addition, we will assess possible mediating mechanisms by measuring markers of hypoxic stress (VEGF), oxidative stress (urinary isoprostane), and markers of sympathetic and hypothalamic-pituitary-adrenal axis function (heart rate variability, urinary norepinephrine, urinary cortisol). The proposed study will test, with adequate statistical power, the hypothesis that recent or past SDB (assessed by AHI, hypoxemia index) predict incident metabolic syndrome and is related to the degree of insulin resistance (HOMA-IR), and vascular or endothelial dysfunction while controlling for potential confounders or explanatory variables, including the existing and newly acquired covariate information.